This is an application for the renewal of a senior scientist research and mentorship award to provide protected time for Ken Mackie so he can achieve the following goals for his research, mentoring, and career development. Specific research objectives during the next five years include: (1) Obtaining a comprehensive understanding of the mechanisms of CB1 cannabinoid receptor desensitization, (2) Discerning the roles of endogenous and exogenous cannabinoids during two key neurodevelopmental stages (A) during embryonic life and (B) during the adolescent maturation of the prefrontal cortex, (3) Exploring the therapeutic potential of CB2 cannabinoid receptor functional selectivity in making more effective analgesics and in attenuating cocaine reward, (4) Using simplified experimental systems (primarily cultured autaptic neurons) to address significant, outstanding issues in endocannabinoid-mediated synaptic plasticity. Dr. Mackie's mentoring will focus on mentoring four groups of scientists that encompass the full career spectrum: undergraduates at Indiana University, graduate and medical students at Indiana University, post-doctoral fellows, and junior faculty. His career development will emphasize the incorporation of more powerful imaging, informatic, proteomic, and behavioral tools into his research, as well as continuing to be heavily committed to service (editorial duties, meeting organization, and grant reviews) related to drug abuse research.